Abstract Young pregnant women are at extremely high risk for acquiring HIV in late pregnancy and postpartum. Although the precise mechanisms to explain the high risk of HIV during this time period is unknown, highly diverse vaginal microbial communities and elevated genital inflammation have been associated with increased HIV susceptibility among non-pregnant women. A balanced maternal inflammatory milieu and a Lactobacillus dominated vaginal microbial communities have long been associated with optimal pregnancy outcomes. However, untimely or excessive inflammatory response or diverse microbial communities in the vagina can lead to adverse birth outcomes and/or HIV acquisition in at risk women. With heightened risk of HIV in pregnancy and postpartum, pre-exposure prophylaxis (PrEP) is increasingly being used during these periods but the effects of maternal PrEP use on child health outcomes remains underexplored. Here, we propose to use two unique cohorts of HIV- uninfected pregnant women and their infants from Umlazi, KwaZulu-Natal, including those actively taking PrEP, to better understand their risk factors for adverse birth outcomes and HIV acquisition as well as neonatal morbidity. The specific aims are to: 1) assess whether vaginal microbial taxa or cytokines during gestation predict risk of preterm labor and delivery in women at high risk for HIV. 16S rRNA gene sequencing and multiplex bead arrays will be used to characterize the composition of vaginal microbial communities and soluble biomarkers of genital inflammation in cervicovaginal swabs and SoftCup fluids collected from women at ~12.5-21.5 weeks? gestation and relate these to incident preterm labor and delivery; 2) determine whether increased vaginal microbial diversity and/or inflammation could explain the higher HIV risk during late pregnancy and early postpartum. Microbial communities and cytokines from cervicovaginal swabs and SoftCup fluids collected at 14- 28 weeks? gestation will be compared with those collected late pregnancy (38?40 weeks? gestation) and 14 and 26 weeks postpartum to identify potential drivers of increased susceptibility HIV infection during these periods; and 3) to determine the effects of antiretroviral exposure during gestation and breastfeeding on infant glucose metabolism and innate immunity. Using samples collected from HIV-unexposed infants at 6 weeks and 12 months of age, plasma adipokine and cytokine levels and markers of insulin resistance will be compared in antiretroviral (ARV)-exposed versus unexposed infants. The proposed research is innovative and will, for the first time, determine whether specific vaginal anaerobic microbes and associated inflammation can predict which women will deliver preterm or acquire HIV in our setting. Further, unique cohorts are available to examine the immunological and metabolic effects of maternal ARV use during pregnancy on infant health without HIV exposure, to inform risk-benefit analyses of maternal PrEP. This study has the potential to lead to more refined interventions to mitigate risks of adverse birth outcomes, HIV acquisition and neonatal morbidity.